mm?! 3 ?tr Office at the Secretary Of?ce of the Assistant Secretary for Health Washington, ac. 20201 OCT 7201? The Honorable Robert W. Patterson Acting Administrator Drug Enforcement Administration US Department of Justice 8701 Morrissette Drive Spring?eld, VA 22152 Dear Mr. Patterson: Pursuant to the Controlled Substances Act (CSA), 21 U.S.C. 81 and the Department of Health and Human Services (HHS) is recommending that the substances mitragynine and 7-0H-mitragynine be permanently controlled in Schedule of the CSA. Mitragynine and 7~0H~mitragynine are mu opioid receptor agonists that represent two of the principle constituents of the plant Min-agree speciosa (M. Species-a). commonly referred to as krarom. In assessing the relative abuse potential of mitragynine and LOH- mitragyninc, FDA reviewed and evaluated all of the available data on the abuse potential of mitragynine and 7?OH-mitragynine. In order to conduct a full evaluation of mitragynine and 7- OH-miyragynine, it was necessary to review information on the use of M. sparrow, the only natural source of rnitragynine and 7?OIl-mitragynine. Identi?cation of M. speciosa cannot be accomplished solely through chemical analysis of mitragynine and 7*0H-mitragynine content alone. This is because adulteration of botanical material from any plant with mitragynine and 7- OH-rnitragynine would make its chemical analysis indistinguishable from that of mitragynine and 7-0I-l-rnitragyninc from M. speciosa. Thus, our scheduling recommendation does not include a recommendation for scheduling M. .rpeciosa due to the dif?culty in identifying the plant. Mitragynine and 7?0ll?mitragynine are mu opioid agonists that elicit pharmacological responses that are similar to those produced by other mu opioid agonists, including morphine (Schedule II). In animals, minagynine and 7-OH?mitragynine produce full generalization to morphine in drug discrimination and produce conditioned place preference, indicating these substances are rewarding. In humans, mitragynine and 7-OH-mitragynine (typically as constituents of M. speeiosa) produce classic opioid effects such as euphoria, sedation, and analgesia. These substances also produce an opioid withdrawal upon drug discontinuation. Thus, mittagynine and 7-OPH-mitragynine have a high potential for abuse. The Food and Drug Administration (F DA) and the National Institute on Drug Abuse have also considered the abuse potential of mitragynine and 7-Ol--l?mitragynine. After reviewing the available information, the agencies conclude that mitragynine and 7-0H-mitragynine should be permanently controlled in Schedule I of the GSA. Enclosed is a document prepared by i-?DA?s Controlled Substance Staff that forms the basis for the recommendation. Public Health Service Page 1 BASIS FOR THE RECOMMENDATION T0 CONTROL MITRAGYNINE AND IN SCHEDULE 5 OF THE CONTROLLED SUBSTANCES ACT On August 21., 2014, the Drug Enforcement Administration (DEA) requested that the Department of Health and Human Services (HHS) conduct a medical and scienti?c evaluation of mitragynine and 7-hydroxymitragynine to determine whether these substances should be recommended for control under the Controlled Substances Act (CSA). Mitragynine and 7~0H-mitragynine are mu opioid receptor agonists that represent two of the principle constituents of the plant Mirragyna specinsa (M speciosa), commonly referred to as krarom. DEA also requested an abuse potential evaluation of M. Speciosa. Subsequently, on August 3 i . 2016, DEA published a Notice of Intent (N01) in the Federal Register ?to temporarily schedule the opioids mitragynine and 7-OH-mitragynine into Schedule I, pursuant to the temporary scheduling provisions of the DEA stated that this action was taken ?to avoid an imminent hazard to the public safety" (8i FR 59929). On October i3, 2 t6, DEA withdrew this N01, stating that they had ?received numerous comments from members of the public challenging the scheduling action and requesting that the agency consider those comments and accompanying information before taking further action." DEA also stated they had requested that expedite its scientific and medical evaluation and scheduling recommendation for these substances. which DEA previously requested" (81 FR i0652). In assessing the relative abuse potential of mitragynine and 7-OH-mitragynine, FDA reviewed and evaluated all of the available data on the abuse potential of mitragynine and "ll?OH- mitragynine. In order to conduct a full evaluation of mitragynine and 7-0H?mitragynine. It was necessary to review on the use of M. Speciosa. the only natural source of mitragynine and ?-0lI-mitragynine. As detailed below. however. this scheduling recommendation does not include a recommendation for scheduling M. speciosa, due to the dif?culty in accurately identifying the plant. Identi?cation of M. speciosa cannot be accomplished solely through chemical analysis of mitragynine and 7~OH-mitragynine content alone. This is because adulteration of botanical material from any plant with mitragynine and 7- OH-mitragynine would make its chemical analysis indistinguishable from that of mitragynine and 7-Oli-mitragynine from spectosa. Thus. obtaining unequivocal identification of M. speciosa can only be accomplished through the combined use of chemical analysis of mitragynine and 7-0H-mitragynine (through high?performance liquid chromatography-mass spectrometry) and molecular analysis of the plant substance (through DNA or RNA sequence analysis (Sukrong et al., 2007)). This type ol?confirmatory data related to the identi?cation ofM. speciosa alone is typically unavailable. Thus, this document does not include a scienti?c and medical evaluatioo of botanical speciosa and restricts the evaluation to two of its major chemical components, mitragynine and 7wOH~mitragynine Pursuant to 21 U.S.C. 81 ofthe CSA. the Secretary of HHS is required to consider in a scienti?c and medical evaluation eight factors determinative of control under the CSA. Page 2 BASES FOR THE EON T0 CONTROL SIITRAGYNENE AND 1N I OF THE CONTROLLED SUBSTANCES ACT DNA or RNA sequence analysis, Sukrong et al, 2007). This type of confirmatory data related to the identi?cation ofM. specie-so alone is typically unavailable. Thus, this document does not include a scienti?c and medical evaluation of botanical speciosa and remains the evaluation to two of its major chemical components. mitragvnine and ?-0H?mitragynine. This review evaluates data from the medical and scienti?c literature, from federal government reports, and databases on the subjective reSponses and adverse events that result from use of mitragynine and 7-OH-mitragynine. l. Din c?s Actu- Lon, Foreman. The first factor the Secretary must consider is the actual or relative potential for abuse of ntitragynine and 7-OH~mitragynine. The term ?abuse" is not de?ned in the CSA. However, the legislative history of the CSA suggests the following points in determining whether a particular drug or substance has a potential for abuse?: a. Individuals are taking the substance in amounts suf?cient to create a hazard to their health or to the safety of other individuals or to the community. b. There is signi?cant diversion of the drug or substance from legitimate drug channels. c. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substance. d. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be signi?cant diversions from legitimate channels, signi?cant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. When assessing the abuse potential of a substance. the Secretar}r considers multiple factors, data sources, and analyses. These factors include the prevalence. frequency, and manner of use in the general public and speci?c subpopulations, the amount ot? material that is available for illicit use, as well as evidence relevant to pepulations that may be at particular risk. Animal, human, and epidemiological data are all used in determining a substance's abuse potential. Scienti?cally, a comprehensive evaluation of the relative abuse potential of a substance generally includes consideration of the drug's receptor activity and neurochemical effects, discriminative stimulus efTects. rewarding effects. phannacokinetics. subjective Comprehensive Drug Abuse Prevention and Control Act of I930. HR. Rep. No. Ell-M44. 9 1 st (Long. Sess. 1 0970) reprinted in U.S.C.C.AN. 4566. 4603 Page 3 BASIS FOR THE RECOMMENDATION TO CONTROL AND OF THE CONTROLLED SUBSTAVCES ACT and 7-OH-mitragynine have substantial capability to be a hazard to the health of the user and to the safety of the community. Quintana at Potential {orAbuse at Milragrnine and 7-0H-mr'traggnine: The following conclusions indicate that mitragynine and 7-OH-mitragynine have a potential for abuse: a) There is evidence that individuals are taking mitragynine and 7-OH~rnitragynine in amounts suf?cient to create a hazard to their health or to the safety of other individuals or to the community. b) Mitragynine and LOH-mitragvnine are not available from legitimate drug channels other than for use in scienti?c research, and there is no evidence of signi?cant diversion from such channels. c) There is signi?cant evidence from epidemiological databases and the scienti?c literature that individuals are using mitragynine and 7-OH-mitragynine for abuse purposes. d) The pharmacological effects of mitragynine and 'f-DH-mitragynine are similar to those of morphine, a Schedule I I drug with high potential for abuse. This supports the conclusion that rnitragynine and 7?OH-mitragvnine present a hazard to the health and safety of individuals and the community. 2. surmc svtosncs or a Band The second factor the Secretary must consider is scientific evidence of the pharmacological effects of mitragynine and 7-OH-mitragynine. The scienti?c evidence for these compounds include their receptor activity and functional effects, their effects in animal behavioral studies, their subjective effects in humans, and serious adverse events resulting from their use. antral Nervous [stem ?eets Receptor Activity and Functional Effects Mitragynine and 7-0H?mitragynine have been shown in binding studies to have high affinity for human mu opioid receptors (Ki 233 nM and 4? nM. respectively) (?Kruegel et al.. 20:6). Functional studies with these compounds showed that they are acting as partial agonists in human tissue, with maximal effects in G-protein activation of 34 percent for mitragynine and 47 percent for 7~0H~rnitragynine (Kruegel et 2016). Mu opioid partial agonists are able to produce signi?cant mu Opioid agonist activity, as long as the dose is not increased beyond a certain level. At higher doses. a mu opioid partial agonist may act as an antagonisr. If an individual has been using mu opioid agonist drugs repeatedly and has developed physical Us Page 4 BASIS FOR THE RECOMMENDATION TO CONTROL AND U: i 0? THE CONTROLLED SUBSTANCES ACT agonist, morphine, was tested in the CPP test, it produced a similar preference in animals for the drug~associated side of the cage. These data suggest that mitragynine and ?I-OH?mitragynine produce rewarding properties that are similar to that of a Schedule 11 mo opioid agonist. Activity at Non-Opioid Receptors Activation of Si?? receptors by (a Schedule I hallucinogen) produces head twitches in mice. This behavior is known to be blocked by SHTZ antagonists and by alpha-2 adrenergic antagonists. When mice were pro-treated with mitragynine, there was a dose~dependent reduction in S-MeO-DMT-induced head twitches (Matsumoto et al. . 1997). This suggests that rnitragynine has antagonistic activity at or alpha-2 adrenergic receptors. Development of Tolerance Tolerance is a physiological adaptation in which repeated exposure to a speci?c dose of a drug will result in a lessening of the effects of that drug at the same dose (Cahill et al., 201-6}. The development of tolerance is a well?known phenomenon following chronic administration of mu opioid agonists such as morphine (Schedule ll}. individuals who develop tolerance after long- term use of mu opioid agonists will often- increase the dose of the drug in order to still obtain the desired effects, regardless of whether those effects are therapeutic in nature or include euphoria for abuse purposes. Since tolerance can differentially devel0p to the various effects of a mu opioid agonist, it is possible that an individual may be tolerant to the therapeutic or abuse responses produced by an opioid, but may not yet be tolerant to certain adverse events. This can lead to a situation where a higher dose of a mu opioid agonist taken to overcome tolerance may produce unexpected serious adverse events such as respiratory depression and death (Cahill et al., 2016). i Individuals who chronically use M. sparrow typically develop tolerance. leading to an increase their intake of the drug over time ('Sttwanlert. 1975). When mitragynine was repeatedly administered to mice, tolerance to the antinociceptive effects developed over the course of 5 days (Fakurazi et at, 2013). Similarly, when 7~OH~rnitragynine was given to mice repeatedly for 5 days, there was a significant reduction in the antinociceptive response (Matsurnoto et al., 2005). in each of these studies, the time course and degree of tolerance produced by mitragynine and 7- OH?mitragynine was similar to the development of tolerance produced by the Schedule I mu opioid agonist, morphine. Cross-tolerance was also observed with 7~OH-mitragynine and morphine (Matsumoto et 2005). Thus, once tolerance developed to one drug (such that a larger dose was necessary to produce analgesia), then a larger dose of the other drug was also needed in that animal to produce analgesia. This phenomenon occurs when drugs have overlapping mechanisms of action. Thus, these results suggest that 7?OH?mitragyninc has run opioid agonist effects similar to that of morphine. Page 6 casts FOR tin: accostsissosnos to courses at: asp minnoxrsu mount; IN scnruur I or tin: cosraourn arr mitrasulgynine, corynantheidaline. corynantheidine. isocorynoxeine, 9-methoxymitralactonine. and mitralactoni-nc. Mitragynine is known chemically as 2,l2b-octahydro-3? acid methyl ester (CAS number 4098-40-2). It has a molecular formula of Cgil'lmNzOn a molecular weight of 398.5: and is soluble in acetone, acetic acid, alcohols. chloroform, and diethyl ether. it is found as white, amorphous with a melting point of 102?- 06 7?OH-mitragynine is known chemically as 2bS)-3-ethyl- .2.3.4,6.7,7a.12b- acid methyl ester (CAS number 174418-824). it has a molecular formula a molecular weight of The solubility. appearance, and melting point of this substance were not characterized. The ?rst total of mitragynine was performed by Takayama et al. (1995). Subsequently, a complete of mitragynine was described using (Ma et al., 2007; Ma et al., 2009), an uncommon starting material. Total of mitragynine involves up to 23 steps, is time-consuming, and is not economical because it produces a low yield (- 3~ l3%) et al., 2012). Thus, total of mitragynine is unlikely to occur in order to support an illicit market. Therefore, use of botanical M. .tpeciosa, or isolation of mitragynine and 7-OH-mitragynirte from M. speciosa. is a more accessible source of the drug for users. Levels of Mtt?mgzning and in M. speciosg The content of mitragynine found naturally in M. speciosa is variable. The total alkaloid content in M. speciosa leaves usually ranges from 0.5 to 1.5 percent (Hassan et al.. 2013). Plants from Thailand were found to have a mitragynine content of 66 percent of the total alkaloid contents (or approximately 3-9 in the raw leaves), while leaves from trees in Malaysia were found to have a mitragynine content of 12 percent of the total alkaloid contents (Takayama et al., 1998; Chittrakam et al., 2008; Ponglux et al., Hassan et al., 2013; Harun et al., 2015). In contrast, the 7~0Humitragynine content comprises up to L6 percent of the total alkaloid content of the plant (or approximately 0.l?O.3 mag in M. speciosa leaves) (Kruegel ct al.. 2016; Warner et al., 2016; Ponglux et al., 1994). The amount of naturally occurring variations of mitragynine and 7-OH-mitragynine concentrations in M. speciosa leaves is unknown because of the limited number of evaluations. For example, concentrations of mitragynine and 7-OH?mitragynine were high in one raw leaf sample (23.8 rug/g and 0.124 mgx'g, respectively), while concentrations were low in two other raw leaf samples (0-1.6 and 0-0.03 mgr?g, respectively) (Kikura-Hanajiri et al.. 2009). Broad variations of the two alkaloids were also detected in of the 13 ?nished products (powder and resin) ranging from 1.2 to 6.3 percent for mitragynine and from 0.01 to 0.04 percent for those of 7-0l?l?mitragynine. The concentrations of the target compounds in the resin samples were much higher than those in the dried leaves (Ruri ct al.. 2009). The alkaloidal content of M. .tpeciosa appears to depend greatly on factors such as growing environment. plant variety, age of Page 7 EASIS FOR 1 RECUMMIENDATION TU MITRAGYNINE AND IN SCHEDULE I OF THE CONTROLLED SI 35 ANCES ACT rig/ml. with an accuracy of 97-102 percent. it can quantify mitragynine in dried botanical samples and liquid extracts. Phamgcakr?nerics Distribution A pharmacokinetic study with mitragynine was conducted in 10 male users of M. speciosa who were administered a tea made from 40 grams of fresh leaves boiled for hour in 2 liters of distilled water (Trakulsrichai et 31.. 2m 5). Three mitragynine concentrations of tea were pre- pared: 0.1042. 0.166, and 0.]917 mg??ml. Subjects ingested 60 or 120 ml of the tea every day for 7 days. Notably, all subjects reported experiencing tongue numbness upon drinking the tea, which they said was similar to their use of tea made from M. speciosn outside the laboratory. Phannacokinetic measurements were taken on the 8th day following one additional dose of the tea. The doses for the ?rst 7 days plus the ?nal 8th day loading dose were: 6.25 inglday - 12.5 mg (n 3), 6.25 trig/day 6.25 mg (n 9.96 mglday 19.92 mg (n r- 9.96 rug/?day - 9.96 mg (n 3). 11.5 trig/day 23 mg (n The Cmax for mitragynine ranged from 0.0185 rig/ml for the 9.96 mg loading dose and 0. i 05 pg/ml for the 23 mg loading dose. The AUCOHtlast ranged from 0062 pg hr/ml for the 9.96 mg loading dose to 0.67 pg for the 23 mg loading dose. Both parameters showed linear phannacokinetics. Tmax for mitragynine was determined to be 0.83 i 0.35 hours. with a half? life (tug) of 23 :t 16 hours. The authors caution that these data may not be representative of individuals who do not have chronic experience with M. speciosa. No other phannacoltinetic studies were conducted in humans that evaluate mitragynine or 7-OH-mitragynine. However, Ramanathan et al. (2015) caution that mitragynine may have pharmacokinetic variability based on its hydrophobicity, poor water solubility. high variability of drug release in simulated biological ?uids, and acid-degradable characteristics. Metabolism In humans, rnitragynine produces 7 phase metabolites through hydrolysis ot'the methylester in position 16, O-demethylation of the 9-methoxy group and of the l'l-rnethoxy group (Philipp et al., 2009). This is then followed by oxidation to carboxylic acids or reduction to alcohols. Three metabolites were additionally conjugated to glucuronides. wreath: Accepted Medical Us; FDA approves medical use of a drug following the submission and review of a new drug application (NDA) or biologics license application (BLA). FDA has not approved any drug product containing mitragynine or 7-0H-mitragynine for marketing, and neither ot'these compounds have been studied in humans under an investigational new drug (IND) application. However. FDA approval of an NDA or BLA is not the only means through which a drug can have a currently accepted medical use in treatment in the United States. In general, a drug may Page 8 BASIS FOR THE. RECOHHIENDATION TU CONTROL AND IN SCHEDI. Li?. I 01? THE COKTROLLED ACT There must be adequate and well?controlled studies proving ej?cacy. ?There must be adequate, well?controlled, wel1~dcsigned, well?conducted, and well~docurnented studies, including clinical investigations, by experts quali?ed by scienti?c training and experience to evaluate the safety and effectiveness of drugs, on the basis of which it could be fairly and responsibly concluded by such experts that the substance will have the intended effect in treating a speci?c, recognized disorder." A search of the medical and scienti?c literature shovrs that there are no published papers reporting on standardized clinical studies in which purified mitragynine, puri?ed 7-OH- mitragynine, or M. .rpecr'oso plant-based compounds were administered to evaluate their safety or efficacy. The criteria for an adequate and well-controlled study for purposes of determining the safety and ef?cacy ofa human drug are defined in 21 CFR 314.126. Therefore, there are not adequate. well-controlled studies showing that the substances will have the intended effect in treating a speci?c. recognized disorder. iv. The drug must be accepted by quali?ed experts. ?The drug has a New Drug Application (NDA) approved by the Food and Drug r'deinistration, pursuant to the Food, Drug and Cosmetic Act, 21 1.3.8.0 355. Or. a consensus of the national community of experts, quali?ed by scienti?c training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a speci?c, recognized disorder. A material conflict of Opinion among experts precludes a ?nding of consensus.? This element requires that the national community of experts. quali?ed by scienti?c training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a speci?c, recognized disorder. Medical practitioners who are not experts in evaluating drugs are not quali?ed to determine whether a drug is generally recognized as safe and effective or meets NDA requirements (57 FR 10499-10505). There is no evidence that there is a consensus among quali?ed experts that mitragynine or 7-O'ri? rnitragynine are safe and effective for use in treating a speci?c. recognized disorder. This is related to the fact there are no adequate scienti?c studies showing that mitragynine or 7-Cli- mitragynine are safe and effective in treating a Speci?c, recognized disorder (as discussed above). v. The scientific evidence mus: be widely available. ?In the absence of NBA approval. information concerning the chemistry. pharmacology. toxicology, and effectiveness of the substance must be reported. published. or otherwise widely available, in suf?cient detail to permit experts, quali?ed by scienti?c training and experience to evaluate the safety and effectiveness of drugs, to fairly and responsibly conclude the substance is safe and effective for use in treating a speci?c, recognized disorder." 15 Page 9 BASIS FOR THE RECGMHENDATION 10 CONTROL AND IN 1 OF THE CONTROLLED SUBSTANCES ACT these disorders are often treated in Western countries with pharmaceutical rnu opioid agonists, and both mitragynine and 7-OH-mitragynine are also mu opioid agonists. speciosa also has been used (or abuse purposes to produce euphoria (Suwaniert, l975). Individuals chew l-3 fresh leaves for both abuse and medicinal purposes. reportedly chewing 3-- 10 times a day (Suwanlen. 1975). Amattayalcul (1960) calculated that 20 M. speciosa leaves contain about 17 mg ofmitragynine (0.85 mgfleaf). As would be eXpected from a mu opioid agonist that is unsCheduled under the SA and easily accessible, M. speciosa is also being used recreationally as an uncontrolled ?legal high? because of its euphorigertic properties (Swogger et al.. 20l 5; Warner et at. 2016). The ?fth factor the Secretary must consider is the scope. duration. and significance ot'abuse of mitragynine and 7?OH-mitragynine. Evidence from DEA reports and published reports in the scienti?c literature demonstrate the scope, duration, and signi?cance of abuse of mitragynine and 7?OH-mitragynine. Availgb?ig at Mitt-331M119 and 7-0H?mr?tragym?ne The primary source of mitragynine and 7-0H-mitragynine in the United States is through Internet sales of specioso (Prozialeck et al., 20 2; Logan et al.. 20 2, Hillebrand el al., 2010; Babu et al., 2008; Rosenbaurn et al., 20! 2; Schmidt et al., 201 although it is also sold in brick- and-mortar shops. The most common forms of speciosa sold by online vendors are powders, capsules, resin extracts, crushed leaves, and tablets (Warner et al., 20l6). Although M. specieso is often marketed as a dietary supplement (Boyer et al.. 2007; Boyer et al., 2008; and Sheleg and Collins, 201 1). there is currently no evidence that it is being sold through any of the corporate nutritional supplement chain stores in the United States (Prozialeck et al.. 2MB) Pgr'sort Comm! Center [lemming The Center for Disease Control and Prevention (CDC) analyzed data from the National Poison Data System (NPDS) for reports of exposure to M. specioso over the period of January 20 0 through December 5. The NPDS is maintained by the American Association of Poison Control Centers and rec0rds data from poison control center calls received across the United States (including 50 states, the District of Columbia, and Puerto Rico (Anwar et al., 2016)). During the 6-year period of 2010 to 20 5. there were a total of 660 calls related to kratorn exposure. The number of calls each year rose from 2015, a 10-fold increase. Cases resulting in consultation with a health professional represented 75 percent of the calls (n 496). Cases that represented non?life threatening complications. with no residual disability, were reported for 42 percent of the calls (n 275}. Potentially complications, some with residual disability. were reported for 7 percent of the calls (it 49). l? Page10 BASIS FOR THE RECOMMENDATION T0 CONTROL AND IN 1 OF THIS ACT the Act (21 U.S.C. because they contain a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a signi?cant or unreasonable risk of illness or injury. Kratom is a botanical that quali?es as a dietary ingredient under section 201(1?00 of the Act (21 U.S.C. 32 D. When marketed as a dietary ingredient. FDA also considers kratom to be a new dietary ingredient under section 413(d) of the Act ('21 [3.5.0 350b(d)) because, to the best of the Agency's knowledge, there is no information demonstrating that this substance was marketed as a dietary ingredient in the United States before October l5, 1994. Furthermore, based on FDA's review of the publicly available information regarding kratont, there does not appear to be a history of use or other evidence of safety establishing that kratotn will reasonably be expected to be safe as a dietary ingredient, in the absence of a history of use or other evidence of safety establishing that kratorn will reasonably be expected to be safe as a dietary ingredient, kratom and kratomcontaining dietary supplements and bulk dietary ingredients are adulterated under section 402(f)(1)(B) of the Act (2i U.S.C. because they contain a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a signi?cant or unreasonable risk of illness or injury. As explained in import Alert 54-15. shipments of kratom and kratom-containing dietary supplements and bulk dietary ingredients may be refused admission pursuant to 2i 381(a)(3) and section 801 of the Act in that they appear to be a dietary supplement or contain a dietary ingredient that is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a signi?cant or unreasonable risk of illness or injury (section These shipments have come in a variety of forms, including capsules, whole leaves. processed leaves, leaf resins, leaf extracts, powdered leaves, and bulk liquids made of leaf extracts. lmporters' websites have sometimes contained information about how their products are used. Districts were also alerted to the possibility that the labeling, marketing, and promotion of kratom and kratom-containing products may indicate that such products appear to be unapproved and misbranded drugs. For such products, Districts were advised that Import Alert 66-41 (?Detention Without Physical Examination of Unapproved New Drugs Promoted in the may be applicable. FDA Enforcement Actions FDA has requested the following seizures of kratorn products in the United States: I in August 2016, at the request of FDA, the U.S. Marshals Service seized more than 100 cases of products labeled as containing kratom. The seized kratorn products were marketed as unapproved new drugs and misbranded drugs in violation of the Act. 0 In September 20l 4, at the request of FDA, the US. Marshals Service seized more than 25,000 pounds of raw kratom material that was marketed as an unapproved new drug and a misbranded drug in violation of the Act. 19 Page 11 BASIS FOR THE RECOMMENDATRON TO CONTROL MITRAGYNIXE AND 513:}; IN 1 OF THE CONTROLLED ACT Subjecrive responses to specioso leaves are dose-dependent, such that low to moderate doses (1?5 3) produce a stimulating effect, while moderate to high doses (54 5 g) produce mu opioid agonistvlike analgesia, euphoria. constipation, and sedative-like effects (Sabetghadam et al., 2013; Jansen and Prast, 1988). While new users of M. specioso may be able to achieve desired effects by chewing just a few leaves, more experienced users apparently have to increase their dosage to 10-30 leaves or more due to tolerance development. Heavy users may have to chew M. speciosa between three and ten times per day. Effects begin within 5-10 minutes after speciosa is consumed and persist for several hours (Hassan et al.. 2013). Regular M. specroso use is associated with addictive disorders. as evidenced by craving and compulsive use (Singh, 20M). Egr'le?r?c Seigares Associated with Mitreggnine and M. sgeer'osa The medical literature contains three reports ofepileptic seizures following speciosa use: - Seizures followed by coma were reported in a 64-year-old man 30 minutes after Speciosa was used in combination with the anticholinergic plant Datum for treatment of pain and reducing opioid withdrawal Following arrival at the emergency department (ED). the man experienced a second seizure. Urine drug screening was positive for cannabinoids, tricyclic antidepressants. and oxycodone. A urine specimen analyzed by detected a mitragynine concentration of 167 i 15 ngr?rnl (Nelsen et al., 20l0). I Seizures were reported after .M. speciosn was used to reduce Opioid withdrawal in combination with modafmil (Boyer et al., 2008). 0 Seizures and foaming at the mouth were reported in a 32-year~old man after recreational M. speciosa use. Toxicology screens were negative for other commonly used recreational drugs Roche et 31., 2009). Liver Abnormalities with Mirronm'ne and M. speciosa There are two case reports in which M. speciosa use resulted in liver damage. 0 A 58?year-old man with schizoaiTective disorder experienced jaundice and liver injury on two separate occasions (separated by a year apart) following regular use of powdered M. speciosa for anti-anxiety purposes (Dorman et 2015). in both instances. the man continued taking his medication, which was identified as quetiapine 100 mg daily) in the first instance and (50 mg daily) in the second instance. Liver bilirubin. ammonia, and enzyme levels were all determined to be abnormal and medication was discontinued temporarily. Upon discontinuation of specimen in both instances, liver tests were returning to normai after several days. Evaluation of body ?uids for mitragynine and 7-0H-mitragynine was not conducted. Page 12 BASIS FOR THE RECOMMENDATION TO CONTROL MURAGYNINE AND 1N SCHEZDI OF THE CONTROLLED AC1 - Antihistamines (promethazine, and alimemazine: 6 of 23 cases; 23%) Cannabinoid 5 of23 cases; 22%) a Stimulants (amphetamine and propylhexedrine; a 4 of 33 cases; 17%) Antiepilepties (gabapentin. carbamazepine. lamotrigine, and dit'alproex: 4 of 23 cases; 17%) (quetiapine and olanzapine; 3 of 23 cases; 13%) Muscle relaxants (carisoprodol and cyclobenzaprine: 2 of 23 cases; Hallucinogen (dimethoxyamphetamine; 2 of 23 cases; Non-steroidal anti-in?ammatory (phenazone; 0123 cases; Cough suppressant (dextromethorphan; of 2.3 cases; Of the 24 fatal cases associated with mitragynine, 7 were published as case reports in the medical literature. These 5 published reports demonstrate the variety of multiple drugs taken in conjunction with mitragynine, which include: folio)? . . .. a Venlafaxine, and minazapine (all at therapeutic levels); in addition. ethanol (peripheral blood ethanol level of 0.02 0/0) and mitragynine. Mitragynine was present in all ?uids and tissue examined (peripheral blood 0.23 mgr?l, central blood 0.19 mg/l, liver tissue 0.43 rug/kg, urine 3 0.37 mg/l). The cause of death of the 24- year-old male was ruled to be ?mixed drug intoxicationmprirnarily mitragynine? (McIntyre et al., 2015). - Propylhexedrine (a stimulant in decongestant inhalers that was previously in Schedule but was decontrolled in 1991), morphine. promethazine, acetaminophen, and mitragynine. Mitragynine was present in plasma (0.39 trig/l). Cause of death was ruled to be the result of propylhexedrine toxicity rather than mitragynine exposure because there were, at that time, no published toxic levels of mitragynine (Holler et alBenzodiazepines and over-the-counter cold medications as well as mitragynine. Mitragynine was present in peripheral blood (0.60 mg/l). The 17-year-old male decedent had a history of heroin abuse and was reportedly using M. speciosa to treat chronic back pain. Cause of death was ruled to be "possible kratom toxicity" (Neerrnan et al., 2013). I Zopiclone, citalopram, and lamotrigine (all at therapeutic levels) in addition to high concentrations of rnitragynine (l .06 mgfl) and ?ll-hydroxyrnitragynine (0.15 mgz'l). Cause of death was ruled to be the result of speeiosa exposure to mitragynine and 7-Cli- rnitragynine (Karinen et al., 2014). asst Leperamide (at high doses) and marijuana in conjunction with mitragynine. Mitragynine was present in plasma (0.6 mg/l) and in liver tissue (0.68 and 3.5 Cause of death in two married individuals (a 33-year-old and a 37-year?old of unreported gender) was judged to be primarily due to loperamide (Bishop-Freeman et 31., 2016). Page 13 BASES FOR RECOMMENDATION TO CONTROL MITRAGYNINE AND IN I OF THE: CONTROLLED ACT muscular pain, itching, cramps, joint pain, diarrhea. restlessness. tension, hostility. aggression, sadness, nervousness, delusion, hallucination, anxiety, depression. moodiness, annoyance, sleeplessness, and intense craving (Suwanlert, l975; Saingam et al., 2013: Saingam et al., 2014; Saingam et al., 20l6; Suwanlert, 1975; Vicknasingam et al., 2010; l-iassan et al., 2013: Assanangkornehai et al., 2007a; Ahmad and Aziz, 20! 2: Singh et al., 2014}. In many cases, long- term users had dif?culty in giving up regular use (Suwanler?t, 1975; Singh et al., 2014). The following case reports were published in the medical literature regarding individuals who developed physical dependence after chronic use of M. speeiosa. These individuals include: . - A 37-year-old woman with a history of chronic use ot?M. speeioso experienced severe opioid-like withdrawal when she discontinued use. Her were managed with clonidine and hydroxyzine (Galbis-Reig. 2016). A man with alcohol dependence and a history of chronic use of M. speciosa reported opioid~like withdrawal when he discontinued use. is included anxiety, restlessness, tremor. sweating, craving, itch. and feelings of dread. The were reported as being ?short and benign" (MeWhirter and Morris, 2010). A patient with a history of chronic use of M. speeiosa (in addition to hypothyroidism) who reported opioid?like withdrawal when use was discontinued. These which resolved within 3 days. included cramping, abdominal pain. sweating, diarrhea, confusion, and delusion (Sheleg and Collins, 2011). A 44-year-old man who used speciosa for 3 years was seen in the ED seeking substance abuse treatment. At that time. he was consuming approximately 40 grams of speeiosa divided into 4 doses over 24 hours. He reported withdrawal of cravings, anxiety, restlessness, sweating, and itching. Oral fluids were negative for amphetamines, benzodiazepines, cocaine metabolites, methadone, and opiates (McWhirter and Morris. 2010). 8. WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECIJRSOR 0F ASEBSTANCE ALREADY CONTROLLED UNDER YHIS ARTICLE The eighth factor the Secretary must consider is whether mitragynine and 7-0l-l-mitragynine are immediate precursors of a controlled substance. Mitragynine and 7'0H4-mitragynine are not immediate precursors, as de?ned by 21 U.S.C. 802(23), of any substance already controlled in the SA. Fa) Ur Page 14 users wit me ascomisxns'nox 'ro censor. man seasons: I or rm: cannons? scesuxces ACT Altemately, a Schedule 11 drug can be considered to have a ?currently accepted medical use With severe restrictions? (21 U.S.C. Yet as stated above, the lack of accepted medical use for a speci?c, recognized disorder precludes the use of mitragynine or 7-OH?mitragynine even under conditions where its use is severely restricted. (C) There is a lack of accepted safety for use of the drug or other substance under medical supervision. Since mitragynine and 7~OH~mitragynine have no approved medical use and have not been investigated as new drugs, their safety for use under medical supervision has not been determined. Thus. there is a lack of accepted safety for use ot?mitragynine and 7?Ol-i~ mitragynine under medical supervision. FDA therefore recommends that mitragynine and 7-OH-mitragynine be controlled in Schedule I of the SA. NIDA concurs with this recommendation. 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